Our laboratory investigations are focused on identifying genes that regulate growth, differentiation, and programmed cell death of normal and malignant mammary epithelial cells in order to develop rational strategies for the treatment of breast cancer. We have several ongoing projects: (1) We have identified several protein tyrosine phosphatases expressed in breast cancer cells and expression of one of these protein tyrosine phosphatases (DEP-1) is increased when breast cancer cells are induced to differentiate in vitro. Over-expression of DEP-1 inhibits the growth of breast cancer cells in culture (Keane et al., Cancer Research, In Press). Further studies are underway to elucidate the mechanism by which DEP-1 inhibits breast cancer cell growth. (2) We have cloned cbl-b, a new SH3 binding protein with homology to the c-cbl proto-oncogene (Keane et al., Oncogene 10, 2367-2377, 1995). Cbl-b and c-cbl are novel signal transduction molecules downstream of receptor tyrosine kinases. Studies in the nematode C. elegans suggest that the cbl/cbl-b homologue is a suppressor of EGF receptor signaling. Ongoing work is focused on elucidating the role that cbl-b plays in the growth stimulation mediated by the EGF family of receptor tyrosine kinases in mammary epithelial cells. We have demonstrated that cbl-b associates with the EGF receptor and are now investigating the biological consequences of this interaction. (3) We have demonstrated that the Fas protein, a membrane receptor capable of triggering apoptosis, is expressed at high levels on normal mammary epithelial cells but only at low levels in breast cancer cells. Additional experiments have shown that the receptor can induce apoptosis in the normal mammary epithelial cells but not in breast cancer cells. We have also shown that Fas sensitivity can be induced in breast cancer cells by treatment of the cells with interferon-gamma and this regulation appears to involve multiple components of the Fas pathway (Keane et al., Cancer Research, In Press). Ongoing studies are focused on exploring the normal physiologic role of Fas in mammary epithelial cells, the relationship of malignant transformation and the Fas pathway, and the modulation of the Fas pathway in breast cancer cells in vitro and in vivo.